Abstract
BackgroundAccurate HLA typing at amino acid level (four-digit resolution) is critical in hematopoietic and organ transplantations, pathogenesis studies of autoimmune and infectious diseases, as well as the development of immunoncology therapies. With the rapid adoption of genome-wide sequencing in biomedical research, HLA typing based on transcriptome and whole exome/genome sequencing data becomes increasingly attractive due to its high throughput and convenience. However, unlike targeted amplicon sequencing, genome-wide sequencing often employs a reduced read length and coverage that impose great challenges in resolving the highly homologous HLA alleles. Though several algorithms exist and have been applied to four-digit typing, some deliver low to moderate accuracies, some output ambiguous predictions. Moreover, few methods suit diverse read lengths and depths, and both RNA and DNA sequencing inputs. New algorithms are therefore needed to leverage the accuracy and flexibility of HLA typing at high resolution using genome-wide sequencing data.ResultsWe have developed a new algorithm named PHLAT to discover the most probable pair of HLA alleles at four-digit resolution or higher, via a unique integration of a candidate allele selection and a likelihood scoring. Over a comprehensive set of benchmarking data (a total of 768 HLA alleles) from both RNA and DNA sequencing and with a broad range of read lengths and coverage, PHLAT consistently achieves a high accuracy at four-digit (92%-95%) and two-digit resolutions (96%-99%), outcompeting most of the existing methods. It also supports targeted amplicon sequencing data from Illumina Miseq.ConclusionsPHLAT significantly leverages the accuracy and flexibility of high resolution HLA typing based on genome-wide sequencing data. It may benefit both basic and applied research in immunology and related fields as well as numerous clinical applications.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-325) contains supplementary material, which is available to authorized users.
Highlights
IntroductionAccurate Human Leukocyte Antigen (HLA) typing at amino acid level (four-digit resolution) is critical in hematopoietic and organ transplantations, pathogenesis studies of autoimmune and infectious diseases, as well as the development of immunoncology therapies
Accurate Human Leukocyte Antigen (HLA) typing at amino acid level is critical in hematopoietic and organ transplantations, pathogenesis studies of autoimmune and infectious diseases, as well as the development of immunoncology therapies
High resolution HLA typing is essential in many areas of immunology, such as hematopoietic stem cell transplant, immunogenic screening and vaccine design
Summary
Accurate HLA typing at amino acid level (four-digit resolution) is critical in hematopoietic and organ transplantations, pathogenesis studies of autoimmune and infectious diseases, as well as the development of immunoncology therapies. Polymorphisms in the HLA loci often result in differences in the amino acid sequences of HLA proteins. This HLA diversity allows a wide range of different antigens to be presented to immune cells within a population. These variations in HLA sequence result in histoincompatibility of organs and tissues between individuals, greatly complicating surgical transplantation of organs and tissues. The risk of graft-versus-host disease and organ or tissue rejection can be minimized if the alleles present at the HLA loci of a perspective donor and recipient encode matching HLA proteins, to the extent possible [4,5]. An individual’s HLA type at an HLA locus is made up of the two HLA alleles (or two copies of a single HLA allele if homozygous) present at the individual’s two copies of the HLA locus
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